Anti-hypersensitive effect of angiotensin (1-7) on streptozotocin-induced diabetic neuropathic pain in mice
- 31 March 2019
- journal article
- research article
- Published by Wiley in European journal of pain
- Vol. 23 (4), 739-749
- https://doi.org/10.1002/ejp.1341
Abstract
Background We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)-induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1-7), an N-terminal fragment of Ang II, may attenuate the Ang II-induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1-7) can attenuate STZ-induced diabetic neuropathic pain. Methods Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho-p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. Results The i.t. administration of Ang (1-7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1-7), whose effect was reversed by A779. Conclusions Our data demonstrate that Ang (1-7) attenuates STZ-induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. Significance: The ACE2/Ang (1-7)/Mas receptor axis was down-regulated in the spinal cord of STZ mice and the i. t. administration of Ang (1-7) attenuated the STZinduced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.Funding Information
- Hirosaki University
- Japan Society for the Promotion of Science (17K08313, 16K21311)
This publication has 52 references indexed in Scilit:
- Angiotensin-(1-7)/Mas receptor as an antinociceptive agent in cancer-induced bone painPain, 2016
- Ang-(1–7) activates the NO/cGMP and ATP-sensitive K+ channels pathway to induce peripheral antinociception in ratsNitric Oxide, 2014
- Potential Role of Sodium-Proton Exchangers in the Low Concentration Arsenic Trioxide-Increased Intracellular pH and Cell ProliferationPLOS ONE, 2012
- Immunohistochemical localization of the angiotensin-(1–7) receptor Mas in the murine forebrainCell and tissue research, 2012
- Prevalence and Characteristics of Painful Diabetic Neuropathy in a Large Community-Based Diabetic Population in the U.K.Diabetes Care, 2011
- Attenuation of isoproterenol-induced cardiac fibrosis in transgenic rats harboring an angiotensin-(1-7)-producing fusion protein in the heartTherapeutic Advances in Cardiovascular Disease, 2010
- The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic InhibitionJournal of Managed Care Pharmacy, 2007
- Epidemiology, Public Health Burden, and Treatment of Diabetic Peripheral Neuropathic Pain: A ReviewPain Medicine, 2007
- Diabetes-Induced Mechanical Hyperalgesia Involves Spinal Mitogen-Activated Protein Kinase Activation in Neurons and Microglia via N-Methyl-D-aspartate-Dependent MechanismsMolecular Pharmacology, 2006
- Spinal pharmacology of tactile allodynia in diabetic ratsBritish Journal of Pharmacology, 1997